title: Identification of potent, noncovalent fatty acid amide hydrolase (FAAH) inhibitors.
abstract: Starting from a series of ureas that were determined to be mechanism-based inhibitors of FAAH, several spirocyclic ureas and lactams were designed and synthesized. These efforts identified a series of novel, noncovalent FAAH inhibitors with in vitro potency comparable to known covalent FAAH inhibitors. The mechanism of action for these compounds was determined through a combination of SAR and co-crystallography with rat FAAH.
authors.affiliation: Department of Chemistry, Amgen Inc., South San Francisco, 1120 Veterans Blvd., South San Francisco, CA 94080, USA. dgustin@amgen.com
authors.forename: Darin J
authors.initials: DJ
authors.lastname: Gustin
authors.forename: Zhihua
authors.initials: Z
authors.lastname: Ma
authors.forename: Xiaoshan
authors.initials: X
authors.lastname: Min
authors.forename: Yihong
authors.initials: Y
authors.lastname: Li
authors.forename: Christine
authors.initials: C
authors.lastname: Hedberg
authors.forename: Cris
authors.initials: C
authors.lastname: Guimaraes
authors.forename: Amy C
authors.initials: AC
authors.lastname: Porter
authors.forename: Michelle
authors.initials: M
authors.lastname: Lindstrom
authors.forename: Dianna
authors.initials: D
authors.lastname: Lester-Zeiner
authors.forename: Guifen
authors.initials: G
authors.lastname: Xu
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Carlson
authors.forename: Shouhua
authors.initials: S
authors.lastname: Xiao
authors.forename: Cesar
authors.initials: C
authors.lastname: Meleza
authors.forename: Richard
authors.initials: R
authors.lastname: Connors
authors.forename: Zhulun
authors.initials: Z
authors.lastname: Wang
authors.forename: Frank
authors.initials: F
authors.lastname: Kayser
mesh_terms: D000581:Amidohydrolases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics; D006801:Humans; D007769:Lactams / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D013141:Spiro Compounds / Q000737:chemistry; D013329:Structure-Activity Relationship; D014508:Urea / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics; D000099252:Fatty Acid Amide Hydrolases
chemical_list: D000581:Amidohydrolases; D004791:Enzyme Inhibitors; D007769:Lactams; D013141:Spiro Compounds; D014508:Urea; D000099252:Fatty Acid Amide Hydrolases